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Blood Apr 2023A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are prominent features in patients with sickle cell disease (SCD)....
A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are prominent features in patients with sickle cell disease (SCD). Coagulation factor XII (FXII) triggers activation of the contact system that is known to be involved in both thrombosis and inflammation, but not in physiological hemostasis. Therefore, we investigated whether FXII contributes to the prothrombotic and inflammatory complications associated with SCD. We found that when compared with healthy controls, patients with SCD exhibit increased circulating biomarkers of FXII activation that are associated with increased activation of the contact pathway. We also found that FXII, but not tissue factor, contributes to enhanced thrombin generation and systemic inflammation observed in sickle cell mice challenged with tumor necrosis factor α. In addition, FXII inhibition significantly reduced experimental venous thrombosis, congestion, and microvascular stasis in a mouse model of SCD. Moreover, inhibition of FXII attenuated brain damage and reduced neutrophil adhesion to the brain vasculature of sickle cell mice after ischemia/reperfusion induced by transient middle cerebral artery occlusion. Finally, we found higher FXII, urokinase plasminogen activator receptor, and αMβ2 integrin expression in neutrophils of patients with SCD compared with healthy controls. Our data indicate that targeting FXII effectively reduces experimental thromboinflammation and vascular complications in a mouse model of SCD, suggesting that FXII inhibition may provide a safe approach for interference with inflammation, thrombotic complications, and vaso-occlusion in patients with SCD.
Topics: Animals; Mice; Anemia, Sickle Cell; Factor XII; Inflammation; Stroke; Thrombosis
PubMed: 36706361
DOI: 10.1182/blood.2022017074 -
Blood Apr 2018Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The factor... (Review)
Review
Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The factor XII-driven contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. Challenging the concept of the coagulation balance, targeting factor XII or its activator polyphosphate, provides protection from thromboembolic diseases without interfering with hemostasis. This suggests that the polyphosphate/factor XII axis contributes to thrombus formation while being dispensable for hemostatic processes. In contrast to deficiency in factor XII providing safe thromboprotection, excessive FXII activity is associated with the life-threatening inflammatory disorder hereditary angioedema. The current review summarizes recent findings of the polyphosphate/factor XII-driven contact system at the intersection of procoagulant and proinflammatory disease states. Elucidating the contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory disorders.
Topics: Angioedemas, Hereditary; Factor XII; Humans; Inflammation; Polyphosphates; Thromboembolism; Thrombosis
PubMed: 29483100
DOI: 10.1182/blood-2017-04-569111 -
The Journal of Experimental Medicine Apr 2012Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an...
Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features.
Topics: Animals; Blood Platelets; Cell Communication; Factor XII; Mice; Mice, Inbred C57BL; Monocytes; Neutrophils; P-Selectin; Thromboplastin; Venous Thrombosis
PubMed: 22451716
DOI: 10.1084/jem.20112322 -
Biochimica Et Biophysica Acta.... Jan 2022The plasma protein factor XII (FXII) is the liver-derived zymogen of the serine protease FXIIa that initiates an array of proteolytic cascades. Zymogen activation,... (Review)
Review
The plasma protein factor XII (FXII) is the liver-derived zymogen of the serine protease FXIIa that initiates an array of proteolytic cascades. Zymogen activation, enzymatic FXIIa activity and functions are regulated by interactions with cell receptors, negatively charged surfaces, other serine proteases, and serpin inhibitors, which bind to distinct protein domains and regions in FXII(a). FXII exerts mitogenic activity, while FXIIa initiates the pro-inflammatory kallikrein-kinin pathway and the pro-thrombotic intrinsic coagulation pathway, respectively. Growing evidence indicates that FXIIa-mediated thrombo-inflammation plays a crucial role in various pathological states besides classical thrombosis, such as endothelial dysfunction. Consistently, increased FXIIa levels are associated with hypercholesterolemia and hypertriglyceridemia. In contrast, FXII deficiency protects from thrombosis but is otherwise not associated with prolonged bleeding or other adverse clinical manifestations. Here, we review current concepts for FXII(a)-driven vascular inflammation focusing on endothelial hyperpermeability, receptor signaling, atherosclerosis and immune cell activation.
Topics: Angioedema; Animals; Atherosclerosis; Endothelium, Vascular; Factor XII; Factor XII Deficiency; Humans; Inflammation
PubMed: 34699874
DOI: 10.1016/j.bbamcr.2021.119166 -
Current Opinion in Hematology Sep 2022Factor XII (FXII), the precursor of the protease FXIIa, contributes to pathologic processes including angioedema and thrombosis. Here, we review recent work on... (Review)
Review
PURPOSE OF REVIEW
Factor XII (FXII), the precursor of the protease FXIIa, contributes to pathologic processes including angioedema and thrombosis. Here, we review recent work on structure-function relationships for FXII based on studies using recombinant FXII variants.
RECENT FINDINGS
FXII is a homolog of pro-hepatocyte growth factor activator (Pro-HGFA). We prepared FXII in which domains are replaced by corresponding parts of Pro-HGA, and tested them in FXII activation and activity assays. In solution, FXII and prekallikrein undergo reciprocal activation to FXIIa and kallikrein. The rate of this process is restricted by the FXII fibronectin type-2 and kringle domains. Pro-HGA replacements for these domains accelerate FXII and prekallikrein activation. When FXII and prekallikrein bind to negatively charged surfaces, reciprocal activation is enhanced. The FXII EGF1 domain is required for surface binding.
SUMMARY
We propose a model in which FXII is normally maintained in a closed conformation resistant to activation by intramolecular interactions involving the fibronectin type-2 and kringle domains. These interactions are disrupted when FXII binds to a surface through EGF1, enhancing FXII activation and prekallikrein activation by FXIIa. These observations have important implications for understanding the contributions of FXII to disease, and for developing therapies to treat thrombo-inflammatory disorders.
Topics: Blood Coagulation; Factor XII; Fibronectins; Humans; Kallikreins; Prekallikrein
PubMed: 35916558
DOI: 10.1097/MOH.0000000000000727 -
Current Opinion in Hematology Sep 2018This review describes the contribution of coagulation factor XII (FXII) in sterile inflammation and wound healing, focusing on recently identified roles for zymogen FXII... (Review)
Review
PURPOSE OF REVIEW
This review describes the contribution of coagulation factor XII (FXII) in sterile inflammation and wound healing, focusing on recently identified roles for zymogen FXII in neutrophil functions.
RECENT FINDINGS
Recent studies have identified an important role for FXII in neutrophil trafficking. In particular, following neutrophil activation, autocrine FXII signals through the urokinase plasminogen activator receptor (uPAR) on the neutrophil surface to upregulate neutrophil functions. The sum of these activities leads to neutrophil adhesion, chemotaxis, and neutrophil extracellular (NET) formation. Downregulating FXII-mediated signaling in neutrophils is associated with improved wound healing.
SUMMARY
These recent findings show the sophisticated role of FXII in vivo and create new opportunities for research on the treatment of chronic inflammatory diseases.
Topics: Cell Adhesion; Chemotaxis; Extracellular Traps; Factor XII; Humans; Inflammation; Neutrophil Activation; Neutrophils; Signal Transduction; Urokinase-Type Plasminogen Activator; Wound Healing
PubMed: 29994899
DOI: 10.1097/MOH.0000000000000450 -
Blood Jan 2017Despite the introduction of direct oral anticoagulants (DOACs), the search for more effective and safer antithrombotic strategies continues. Better understanding of the... (Review)
Review
Despite the introduction of direct oral anticoagulants (DOACs), the search for more effective and safer antithrombotic strategies continues. Better understanding of the pathogenesis of thrombosis has fostered 2 new approaches to achieving this goal. First, evidence that thrombin may be as important as platelets to thrombosis at sites of arterial injury and that platelets contribute to venous thrombosis has prompted trials comparing anticoagulants with aspirin for secondary prevention in arterial thrombosis and aspirin with anticoagulants for primary and secondary prevention of venous thrombosis. These studies will help identify novel treatment strategies. Second, emerging data that naturally occurring polyphosphates activate the contact system and that this system is critical for thrombus stabilization and growth have identified factor XII (FXII) and FXI as targets for new anticoagulants that may be even safer than the DOACs. Studies are needed to determine whether FXI or FXII is the better target and to compare the efficacy and safety of these new strategies with current standards of care for the prevention or treatment of thrombosis. Focusing on these advances, this article outlines how treatment strategies for thrombosis are evolving and describes the rationale and approaches to targeting FXII and FXI. These emerging anticoagulant strategies should address unmet needs and reduce the systemic underuse of anticoagulation because of the fear of bleeding.
Topics: Animals; Anticoagulants; Blood Coagulation; Factor XI; Factor XII; Humans; Thrombosis
PubMed: 27780803
DOI: 10.1182/blood-2016-09-692996 -
Seminars in Immunopathology Aug 2021Coagulation is controlled by a delicate balance of prothrombotic and antithrombotic mechanisms, to prevent both excessive blood loss from injured vessels and pathologic... (Review)
Review
Coagulation is controlled by a delicate balance of prothrombotic and antithrombotic mechanisms, to prevent both excessive blood loss from injured vessels and pathologic thrombosis. The liver plays a pivotal role in hemostasis through the synthesis of plasma coagulation factors and their inhibitors that, in addition to thrombosis and hemostasis, orchestrates an array of inflammatory responses. As a result, impaired liver function has been linked with both hypercoagulability and bleeding disorders due to a pathologic balance of pro- and anticoagulant plasma factors. At sites of vascular injury, thrombus propagation that finally may occlude the blood vessel depends on negatively charged biopolymers, such as polyphosphates and extracellular DNA, that provide a physiological surface for contact activation of coagulation factor XII (FXII). FXII initiates the contact system that drives both the intrinsic pathway of coagulation, and formation of the inflammatory mediator bradykinin by the kallikrein-kinin system. Moreover, FXII facilitates receptor-mediated signalling, thereby promoting mitogenic activities, angiogenesis, and neutrophil stimulation with implications for liver diseases. Here, we summarize current knowledge on the FXII-driven contact system in liver diseases and review therapeutic approaches to target its activities during impaired liver function.
Topics: Blood Coagulation; Factor XII; Humans; Kallikrein-Kinin System; Liver; Thrombosis
PubMed: 34125270
DOI: 10.1007/s00281-021-00876-7 -
European Journal of Medicinal Chemistry Dec 2020Coagulation factor XII (FXII), a S1A serine protease, was discovered more than fifty years ago. However, its in vivo functions and its three-dimensional structure... (Review)
Review
Coagulation factor XII (FXII), a S1A serine protease, was discovered more than fifty years ago. However, its in vivo functions and its three-dimensional structure started to be disclosed in the last decade. FXII was found at the crosstalk of several physiological pathways including the intrinsic coagulation pathway, the kallikrein-kinin system, and the immune response. The FXII inhibition emerges as a therapeutic strategy for the safe prevention of artificial surface-induced thrombosis and in patients suffering from hereditary angioedema. The anti-FXII antibody garadacimab discovered by phage-display library technology is actually under phase II clinical evaluation for the prophylactic treatment of hereditary angioedema. The implication of FXII in neuro-inflammatory and neurodegenerative disorders is also an emerging research field. The FXII or FXIIa inhibitors currently under development include peptides, proteins, antibodies, RNA-based technologies, and, to a lesser extent, small-molecular weight inhibitors. Most of them are proteins, mainly isolated from hematophagous arthropods and plants. The discovery and development of these FXII inhibitors and their potential indications are discussed in the review.
Topics: Animals; Anticoagulants; Drug Discovery; Factor XII; Factor XIIa; Humans; Serine Proteinase Inhibitors
PubMed: 32883641
DOI: 10.1016/j.ejmech.2020.112753 -
Journal of Thrombosis and Haemostasis :... Feb 2021Contact activation is triggered when blood is exposed to compounds or "surfaces" that promote conversion of the plasma zymogens factor XII (FXII) and prekallikrein to... (Review)
Review
Contact activation is triggered when blood is exposed to compounds or "surfaces" that promote conversion of the plasma zymogens factor XII (FXII) and prekallikrein to the active proteases FXIIa and kallikrein. FXIIa promotes blood coagulation by converting zymogen factor XI (FXI) to the protease FXIa. Contact activation appears to represent an enhancement of the propensity for FXII and prekallikrein to reciprocally activate each other by surface-independent limited proteolysis. The nature of the activities that perpetuate this process, and that trigger contact activation, are debated. FXII and prekallikrein, like most members of the chymotrypsin/trypsin protease family, are synthesized as single polypeptides that are presumed to be in an inactive state. Internal cleavage leads to conformational changes in the protease domain that convert the enzyme active site from a closed conformation to an open conformation accessible to substrates. We observed that FXII expresses a low level of activity as a single-chain zymogen that catalyzes prekallikrein activation in solution, as well as surface-dependent activation of prekallikrein, FXI, and FXII (autoactivation). Prekallikrein also expresses activity that promotes cleavage of kininogen to release bradykinin, and surface-dependent FXII activation. Modeling suggests that a glutamine residue at position 156 in the FXII and prekallikrein protease domains stabilizes an open active site conformation by forming hydrogen bonds with Asp194. The activity inherent in FXII and prekallikrein suggests a mechanism for sustaining reciprocal activation of the proteins and for initiating contact activation, and supports the premise that zymogens of some trypsin-like enzymes are active proteases.
Topics: Enzyme Precursors; Factor XI; Factor XII; Humans; Prekallikrein; Proteolysis
PubMed: 33107140
DOI: 10.1111/jth.15149